ES2677069T3 - Injection of 5 alpha-androstane (alkyl) -3 beta, 5.6 beta-triol and its preparation method - Google Patents
Injection of 5 alpha-androstane (alkyl) -3 beta, 5.6 beta-triol and its preparation method Download PDFInfo
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- ES2677069T3 ES2677069T3 ES11826361.5T ES11826361T ES2677069T3 ES 2677069 T3 ES2677069 T3 ES 2677069T3 ES 11826361 T ES11826361 T ES 11826361T ES 2677069 T3 ES2677069 T3 ES 2677069T3
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- injection
- cyclodextrin
- hydroxypropyl
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- lyophilization
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- 238000002347 injection Methods 0.000 title claims abstract description 59
- 239000007924 injection Substances 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title description 15
- QZLYKIGBANMMBK-UGCZWRCOSA-N 5α-Androstane Chemical compound C([C@@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CCC[C@@]2(C)CC1 QZLYKIGBANMMBK-UGCZWRCOSA-N 0.000 title description 2
- 125000000217 alkyl group Chemical group 0.000 title description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 239000007788 liquid Substances 0.000 claims abstract description 5
- 239000007787 solid Substances 0.000 claims abstract description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 29
- 229920000858 Cyclodextrin Polymers 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 239000000243 solution Substances 0.000 claims description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 14
- 239000011780 sodium chloride Substances 0.000 claims description 14
- 238000004108 freeze drying Methods 0.000 claims description 13
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- 238000001914 filtration Methods 0.000 claims description 8
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 7
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- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 4
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 4
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- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 4
- 239000000600 sorbitol Substances 0.000 claims description 4
- 235000010356 sorbitol Nutrition 0.000 claims description 4
- 239000000811 xylitol Substances 0.000 claims description 4
- 235000010447 xylitol Nutrition 0.000 claims description 4
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 4
- 229960002675 xylitol Drugs 0.000 claims description 4
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- 229940068918 polyethylene glycol 400 Drugs 0.000 claims description 2
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical compound CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 claims description 2
- 238000001694 spray drying Methods 0.000 claims description 2
- 238000011082 depyrogenation Methods 0.000 claims 3
- 239000012155 injection solvent Substances 0.000 claims 1
- IFRIPYPBJCUNAG-OTMXHXQLSA-N (3s,5r,6r,8s,9s,10r,13s,14s)-10,13-dimethyl-1,2,3,4,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3,5,6-triol Chemical compound C([C@]1(O)[C@H](O)C2)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CCC[C@@]2(C)CC1 IFRIPYPBJCUNAG-OTMXHXQLSA-N 0.000 abstract description 59
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 abstract 1
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
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- 241000700198 Cavia Species 0.000 description 1
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- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000036982 Spinal cord ischaemia Diseases 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
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- 238000011049 filling Methods 0.000 description 1
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- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- -1 steroid compounds Chemical class 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
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Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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Abstract
Una inyección de 5α-androstano-3ß,5,6ß-triol, que incluye una inyección líquida que tiene un disolvente o una inyección sólida, comprende al menos un excipiente soluble, en donde el al menos un excipiente soluble incluye hidroxipropil-ß-ciclodextrina.An injection of 5α-androstane-3ß, 5,6ß-triol, which includes a liquid injection having a solvent or a solid injection, comprises at least one soluble excipient, wherein the at least one soluble excipient includes hydroxypropyl-β-cyclodextrin .
Description
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DESCRIPCIONDESCRIPTION
Inyeccion de 5 alfa-androstano (alquil)-3 beta,5,6 beta-triol y su metodo de preparacion Campo de la invencionInjection of 5 alpha-androstane (alkyl) -3 beta, 5.6 beta-triol and its method of preparation Field of the invention
La presente invencion pertenece al campo de los productos farmaceuticos y se refiere a la inyeccion de 5a-androstano- 3p,5,6p-triol y a su metodo de preparacion.The present invention belongs to the field of pharmaceutical products and refers to the injection of 5a-androstane-3p, 5,6p-triol and its method of preparation.
Antecedentes de la invencionBackground of the invention
El 5a-androstano-3p,5,6p-triol (en lo sucesivo YC-6) es un compuesto neuroprotector recien descubierto. Actualmente, el accidente cerebrovascular isquemico agudo (AIS: Acute Ischemic Stroke) se trata principalmente mediante terapia trombolttica o neuroprotectora. Los agentes neuroprotectores pueden reducir el area del infarto cerebral y evitar las complicaciones hemorragicas que pueden ocurrir durante la terapia trombolttica o anticoagulante. Ademas, pueden usarse incluso sin ningun diagnostico etiologico y hacer posible el tratamiento precoz. Por tanto, los agentes neuroprotectores han atrafdo cada vez mas la atencion en la investigacion del AIS.5a-androstane-3p, 5,6p-triol (hereinafter YC-6) is a newly discovered neuroprotective compound. Currently, acute ischemic stroke (AIS: Acute Ischemic Stroke) is mainly treated by thrombolytic or neuroprotective therapy. Neuroprotective agents can reduce the area of cerebral infarction and avoid bleeding complications that may occur during thrombolytic or anticoagulant therapy. In addition, they can be used even without any etiological diagnosis and make early treatment possible. Therefore, neuroprotective agents have increasingly attracted attention in the investigation of AIS.
Sin embargo, hasta ahora no se ha probado que ningun agente neuroprotector sea seguro y efectivo. Una gran cantidad de compuestos con valor potencial para la aplicacion clmica estan en ensayos cirnicos, incluidos los bloqueadores de los canales de calcio (CCB: Calcium Channel Blockers), moduladores del canal de calcio, inhibidores de la liberacion de glutamato, agonistas del receptor Y-aminobutmco (GABA), eliminadores de radicales libres, anticuerpos de molecula de adhesion anti-intercelular, etc.However, until now no neuroprotective agent has been proven safe and effective. A large number of compounds with potential value for the chemical application are in circus tests, including calcium channel blockers (CCB: Calcium Channel Blockers), calcium channel modulators, glutamate release inhibitors, Y receptor agonists -aminobutmco (GABA), free radical scavengers, anti-intercellular adhesion molecule antibodies, etc.
Entre un gran numero de compuestos, los esteroides neuroactivos son cada vez mas atractivos debido a su amplio efecto de proteccion neuronal. En particular, el efecto del compuesto YC-6, como una entidad qmmica neuroprotectora recien descubierta, no se limita a la proteccion neuronal. Es eficaz no solo contra la isquemia cerebral sino tambien contra la isquemia de la medula espinal a dosis diarias de 50 a 100 mg.Among a large number of compounds, neuroactive steroids are increasingly attractive due to their broad neuronal protection effect. In particular, the effect of compound YC-6, as a newly discovered neuroprotective chemical entity, is not limited to neuronal protection. It is effective not only against cerebral ischemia but also against spinal cord ischemia at daily doses of 50 to 100 mg.
El YC-6 es insoluble en agua. Aunque su solubilidad aumenta en disolventes no acuosos convencionales o mezclas de los mismos, estos disolventes causan irritacion, y podna ocurrir la precipitacion de YC-6 cuando se diluye con agua. La eficacia y la seguridad de la inyeccion de YC-6 se ven afectadas negativamente y su uso es limitado.The YC-6 is insoluble in water. Although their solubility increases in conventional non-aqueous solvents or mixtures thereof, these solvents cause irritation, and YC-6 precipitation may occur when diluted with water. The efficacy and safety of the YC-6 injection are negatively affected and its use is limited.
Se describe en el documento que sigue una hemisuccinacion conocida de hidroxiesteroles: CHEN JINGBO ET AL: "Hemisuccination of Hydroxysterols", HECHENG HUAXUE / CHINESE JOURNAL OF SYNTHETIC CHEMISTRY, CHENGDU YUJI HUAXUESUO, CHINA, vol. 8, no. 5, 8 de mayo de 2000 (), paginas 466 - 468, XP008169327, ISSN: 1005 - 1511.It is described in the document that follows a known hemisuccinacion of hydroxysteres: CHEN JINGBO ET AL: "Hemisuccination of Hydroxysterols", HECHENG HUAXUE / CHINESE JOURNAL OF SYNTHETIC CHEMISTRY, CHENGDU YUJI HUAXUESUO, CHINA, vol. 8, no. May 5, 8, 2000 (), pages 466-468, XP008169327, ISSN: 1005-1511.
El documento WO 97/17992 A1 describe una formulacion conocida para la administracion de compuestos esteroides. Sumario de la invencionWO 97/17992 A1 describes a known formulation for the administration of steroid compounds. Summary of the invention
Para superar las deficiencias expuestas anteriormente, la presente invencion proporciona inyecciones de YC-6 y sus metodos de preparacion. La presente invencion usa hidroxipropil-p-ciclodextrina como agente solubilizante para preparar inyecciones de YC-6. La irritacion causada por disolventes no acuosos se reduce con exito al aumentar la solubilidad del YC-6.To overcome the deficiencies set forth above, the present invention provides injections of YC-6 and its methods of preparation. The present invention uses hydroxypropyl-p-cyclodextrin as a solubilizing agent to prepare injections of YC-6. Irritation caused by non-aqueous solvents is successfully reduced by increasing the solubility of YC-6.
Para lograr esto, se proporcionan inyecciones de YC-6 en forma lfquida o solida. Las inyecciones tienen al menos un excipiente soluble que incluye hidroxipropil-p-ciclodextrina. El al menos un excipiente soluble puede tambien comprender un agente de ajuste isotonico o una carga de liofilizacion.To achieve this, YC-6 injections are provided in liquid or solid form. The injections have at least one soluble excipient that includes hydroxypropyl-p-cyclodextrin. The at least one soluble excipient may also comprise an isotonic adjusting agent or a lyophilization filler.
Preferiblemente, el YC-6 esta presente en una relacion de partes en peso de 1 ~ 20 : 40 ~ 500 respecto a la hidroxipropil-p-ciclodextrina.Preferably, the YC-6 is present in a ratio of parts by weight of 1 ~ 20: 40 ~ 500 with respect to hydroxypropyl-p-cyclodextrin.
Las inyecciones tambien se pueden preparar con los siguientes componentes (en peso): 1 ~ 20 partes de YC-6, 40 ~ 500 partes de hidroxipropil-p-ciclodextrina, 1 ~ 100 partes de un agente de ajuste isotonico, 0 ~ 200 partes de una carga de liofilizacion, y 0 ~ 2000 partes de un disolvente.Injections can also be prepared with the following components (by weight): 1 ~ 20 parts of YC-6, 40 ~ 500 parts of hydroxypropyl-p-cyclodextrin, 1 ~ 100 parts of an isotonic adjusting agent, 0 ~ 200 parts of a lyophilization charge, and 0 ~ 2000 parts of a solvent.
El agente de ajuste isotonico se selecciona del grupo que consiste en cloruro sodico, glucosa, manitol, lactosa, xilitol, sorbitol, maltitol y mezclas de los mismos.The isotonic adjusting agent is selected from the group consisting of sodium chloride, glucose, mannitol, lactose, xylitol, sorbitol, maltitol and mixtures thereof.
La carga de liofilizacion se elige entre el grupo que consiste en cloruro sodico, glucosa, manitol, lactosa, xilitol, sorbitol, maltitol y mezclas de los mismos.The lyophilization load is chosen from the group consisting of sodium chloride, glucose, mannitol, lactose, xylitol, sorbitol, maltitol and mixtures thereof.
Si se va a preparar una inyeccion de lfquido, el disolvente se elige entre el grupo que consiste en propanodiol, etanol, polietilenglicol 400, polietilenglicol 200, glicerol, agua y mezclas de los mismos.If a liquid injection is to be prepared, the solvent is chosen from the group consisting of propanediol, ethanol, polyethylene glycol 400, polyethylene glycol 200, glycerol, water and mixtures thereof.
La inyeccion de la presente invencion se puede preparar mediante un metodo que comprende las etapas de la disolucion de hidroxipropil-p-ciclodextrina, YC-6 y al menos un excipiente soluble en agua para inyeccion en secuencia,The injection of the present invention can be prepared by a method comprising the steps of dissolving hydroxypropyl-p-cyclodextrin, YC-6 and at least one water soluble excipient for sequential injection,
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para obtener una solucion en bruto; y someter la solucion en bruto a decoloracion, filtracion y esterilizacion en secuencia para obtener la inyeccion de la presente invencion.to obtain a raw solution; and subjecting the crude solution to bleaching, filtration and sterilization in sequence to obtain the injection of the present invention.
El polvo de liofilizacion se prepara rellenando una ampolla con un filtrado producido por la etapa de filtracion anterior y sometiendola a liofilizacion.The lyophilization powder is prepared by filling a blister with a filtrate produced by the previous filtration stage and subjecting it to lyophilization.
El polvo esteril se prepara secando por pulverizacion un filtrado producido por la etapa de filtracion anterior, seguido de envasado.The sterile powder is prepared by spray drying a filtrate produced by the previous filtration step, followed by packaging.
La decoloracion puede realizarse usando 0,1 ~ 0,3% de carbon activado y la esterilizacion puede realizarse a 115 °C durante 30 min o a 121 °C durante 15 min.Discoloration can be performed using 0.1 ~ 0.3% activated carbon and sterilization can be performed at 115 ° C for 30 min or at 121 ° C for 15 min.
Se apreciara que el YC-6 se puede formular tambien en infusiones cargadas con YC-6, mezclando la inyeccion de YC-6 con infusiones convencionales libres de farmaco, tales como infusion de glucosa, infusion de cloruro sodico o infusion de glucosa y cloruro sodico.It will be appreciated that YC-6 can also be formulated in infusions loaded with YC-6, mixing the injection of YC-6 with conventional drug-free infusions, such as glucose infusion, infusion of sodium chloride or infusion of glucose and sodium chloride .
La presente invencion es ventajosa sobre las tecnicas convencionales. Los usos de hidroxipropil-p-ciclodextrina o disolventes no acuosos o disolventes mixtos aumentan la solubilidad del YC-6, de modo que el YC-6 se puede preparar en solucion para inyeccion, polvo esteril, polvo de liofilizacion, infusion de glucosa cargada con YC-6, infusion de cloruro de sodio, o infusion de glucosa y cloruro de sodio, que hace posible administrar el YC-6 por inyeccion intravenosa en caso de urgencia. Ademas, el YC-6 tiene suficiente solubilidad y eficacia sin ninguna irritacion cuando se formula en la presente inyeccion. El proceso de preparacion tambien es simple y ampliamente disponible.The present invention is advantageous over conventional techniques. Uses of hydroxypropyl-p-cyclodextrin or non-aqueous solvents or mixed solvents increase the solubility of YC-6, so that YC-6 can be prepared in solution for injection, sterile powder, lyophilization powder, glucose infusion loaded with YC-6, sodium chloride infusion, or glucose and sodium chloride infusion, which makes it possible to administer YC-6 by intravenous injection in case of emergency. In addition, YC-6 has sufficient solubility and efficacy without any irritation when formulated in the present injection. The preparation process is also simple and widely available.
Descripcion detallada de la invencionDetailed description of the invention
Ejemplo 1. Preparacion de 200 ampollas de inyeccion de YC-6 (especificacion 5ml: 50 mg).Example 1. Preparation of 200 injection ampoules of YC-6 (5ml specification: 50 mg).
Formula: YC-6 10 gFormula: YC-6 10 g
2-hidroxipropil-p-ciclodextrina 200 g2-hydroxypropyl-p-cyclodextrin 200 g
Cloruro sodico 1,25 gSodium Chloride 1.25 g
Agua para inyeccion, q.s. para 1000 mlWater for injection, q.s. for 1000 ml
Preparacion: Disolver 2-hidroxipropil-p-ciclodextrina en 80% del agua dulce para inyeccion y agregar YC-6, seguido por agitacion a temperatura ambiente durante 10 ~ 20 minutos para hacer que YC-6 se disuelva completamente. Anadir cloruro de sodio y hacer que se disuelva agitando, anadir luego agua para inyeccion hasta 1000 ml. Anadir 0,1% de carbon activado a la solucion anterior, agitar durante 15 minutos a 60 °C y luego dejar enfriar la solucion a temperatura ambiente. Se usa un filtro de membrana microporosa de 0,22 pm para filtrar. El filtrado se recoge y se envasa para preparar 5 ml de inyeccion, y se somete a esterilizacion a 121 °C durante 15 min.Preparation: Dissolve 2-hydroxypropyl-p-cyclodextrin in 80% of the fresh water for injection and add YC-6, followed by stirring at room temperature for 10 ~ 20 minutes to make YC-6 dissolve completely. Add sodium chloride and dissolve while stirring, then add water for injection up to 1000 ml. Add 0.1% activated carbon to the previous solution, stir for 15 minutes at 60 ° C and then let the solution cool to room temperature. A 0.22 pm microporous membrane filter is used to filter. The filtrate is collected and packaged to prepare 5 ml of injection, and subjected to sterilization at 121 ° C for 15 min.
- Ejemplo 2. Example 2
- Preparacion de 200 ampollas de inyeccion de YC-6 (especificacion 10 ml: 80 mg) Preparation of 200 injection ampoules of YC-6 (specification 10 ml: 80 mg)
- Formula: Formula:
- YC-6 16 g YC-6 16 g
- 3-hidroxipropil-p-ciclodextrina 400 g 3-hydroxypropyl-p-cyclodextrin 400 g
- Glucosa 13,9 g Glucose 13.9 g
- Agua para inyeccion, q. s. para 2000 ml Water for injection, q. s. for 2000 ml
Preparacion: Disolver 3-hidroxipropil-p-ciclodextrina en 80% del agua dulce para inyeccion y anadir YC-6, seguido de agitacion a temperatura ambiente durante 10 ~ 20 minutos para hacer que el YC-6 se disuelva completamente. Anadir la glucosa y disolverla con agitacion, anadir luego agua para inyeccion hasta 2000 ml. Anadir 0,1% de carbon activado a la solucion anterior, y agitar durante 15 minutos a 60 °C, y luego dejar enfriar la solucion a temperatura ambiente. Se usa para filtrar un filtro de membrana microporosa de 0,22 pm. El filtrado se recoge y se introduce para preparar 10 ml de inyeccion, y se somete a esterilizacion a 121 °C durante 15 min.Preparation: Dissolve 3-hydroxypropyl-p-cyclodextrin in 80% of the fresh water for injection and add YC-6, followed by stirring at room temperature for 10 ~ 20 minutes to make the YC-6 dissolve completely. Add the glucose and dissolve it with stirring, then add water for injection up to 2000 ml. Add 0.1% activated carbon to the previous solution, and stir for 15 minutes at 60 ° C, and then let the solution cool to room temperature. It is used to filter a 0.22 pm microporous membrane filter. The filtrate is collected and introduced to prepare 10 ml of injection, and subjected to sterilization at 121 ° C for 15 min.
- Ejemplo 3. Example 3
- Preparacion de 200 ampollas de inyeccion de YC-6 (especificacion 5 ml: 100 mg) Preparation of 200 injection ampoules of YC-6 (5 ml specification: 100 mg)
- Formula: Formula:
- YC-6 20 g YC-6 20 g
- 2-hidroxipropil-p-ciclodextrina 400 g 2-hydroxypropyl-p-cyclodextrin 400 g
- Agua para inyeccion, q. s. para 1000 ml Water for injection, q. s. for 1000 ml
Preparacion: Disolver 2-hidroxipropil-p-ciclodextrina en 80% del agua dulce para inyeccion y anadir el YC-6, seguido de agitacion a temperatura ambiente durante 10 ~ 20 minutos para hacer que el YC-6 se disuelva completamente. Anadir agua para inyeccion hasta 1000 ml. Anadir 0,1% de carbon activado a la solucion anterior, y agitar durante 15Preparation: Dissolve 2-hydroxypropyl-p-cyclodextrin in 80% of the fresh water for injection and add the YC-6, followed by stirring at room temperature for 10 ~ 20 minutes to make the YC-6 dissolve completely. Add water for injection up to 1000 ml. Add 0.1% activated carbon to the previous solution, and stir for 15
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minutos a 60 °C y luego dejar enfriar la solucion a temperatura ambiente. Se usa un filtro de membrana microporosa de 0,22 pm para filtrar. El filtrado se recoge y se llena para preparar 5 ml de inyeccion y se somete a esterilizacion a 115 °C durante 30 min.minutes at 60 ° C and then let the solution cool to room temperature. A 0.22 pm microporous membrane filter is used to filter. The filtrate is collected and filled to prepare 5 ml of injection and subjected to sterilization at 115 ° C for 30 min.
Ejemplo 4. Preparacion de 200 ampollas de polvo esteril de YC-6 (especificacion 80 mg/frasco).Example 4. Preparation of 200 ampoules of sterile powder of YC-6 (specification 80 mg / bottle).
Formula: YC-6 16 g
Formula: YC-6 16 g
2-hidroxipropil-p-ciclodextrina 400 g
2-hydroxypropyl-p-cyclodextrin 400 g
Cloruro sodico 2,5 g
2.5 g sodium chloride
Envasado en 200 ampollasPackaged in 200 ampoules
Preparacion: Disolver 2-hidroxipropil-p-ciclodextrina en 80% del agua dulce para inyeccion y anadir YC-6, seguido de agitacion a temperatura ambiente durante 10 ~ 20 min para hacer que el YC-6 se disuelva completamente. Anadir el cloruro de sodio y hacer que se disuelva agitando, y anadir agua para inyeccion hasta 2000 ml. Anadir 0,1% de carbon activado a la solucion anterior, y agitar durante 15 minutos a 60 °C, y luego dejar enfriar la solucion a temperatura ambiente. Se usa para filtrar un filtro de membrana microporosa de 0,22 pm. El filtrado se somete a secado por pulverizacion y luego se envasa en 200 ampollas.Preparation: Dissolve 2-hydroxypropyl-p-cyclodextrin in 80% of the fresh water for injection and add YC-6, followed by stirring at room temperature for 10 ~ 20 min to make the YC-6 dissolve completely. Add the sodium chloride and make it dissolve by stirring, and add water for injection up to 2000 ml. Add 0.1% activated carbon to the previous solution, and stir for 15 minutes at 60 ° C, and then let the solution cool to room temperature. It is used to filter a 0.22 pm microporous membrane filter. The filtrate is spray dried and then packaged in 200 ampoules.
Ejemplo 5. Preparacion de 200 ampollas de polvo de liofilizacion de YC-6 (especificacion 5 ml: 60 mg).Example 5. Preparation of 200 ampoules of lyophilization powder of YC-6 (specification 5 ml: 60 mg).
- Formula: Formula:
- YC-6 12 g YC-6 12 g
- 3-hidroxipropil-p-ciclodextrina 200 g 3-hydroxypropyl-p-cyclodextrin 200 g
- Glucosa 7 g Glucose 7 g
- Agua para inyeccion, q.s. para 1000 ml Water for injection, q.s. for 1000 ml
Preparacion: Disolver 3-hidroxipropil-p-ciclodextrina en 80% del agua dulce para inyeccion y agregar el YC-6, seguido de agitacion a temperatura ambiente durante 10 ~ 20 minutos para que el YC-6 se disuelva completamente. Agregar la glucosa y disolverla agitando, y anadir el agua para inyeccion hasta 1000 ml. Anadir 0,1% de carbon activado a la solucion anterior, y agitar durante 15 minutos a 60 °C y luego dejar enfriar la solucion a temperatura ambiente. Se usa un filtro de membrana microporosa de 0,22 pm para filtrar. El filtrado se envasa en ampollas de 5 ml y luego se somete a liofilizacion.Preparation: Dissolve 3-hydroxypropyl-p-cyclodextrin in 80% of the fresh water for injection and add the YC-6, followed by stirring at room temperature for 10 ~ 20 minutes for the YC-6 to dissolve completely. Add the glucose and dissolve it while stirring, and add the water for injection up to 1000 ml. Add 0.1% activated carbon to the previous solution, and stir for 15 minutes at 60 ° C and then let the solution cool to room temperature. A 0.22 pm microporous membrane filter is used to filter. The filtrate is packaged in 5 ml ampoules and then subjected to lyophilization.
Ejemplo 6. Estabilidad compatible de la inyeccion de YC-6 e infusiones convencionales.Example 6. Compatible stability of YC-6 injection and conventional infusions.
Se anaden dos ampollas de inyeccion de YC-6 (5 ml X 2) del Ejemplo 1 a infusiones convencionales para evaluar la estabilidad compatible del YC-6 en 8 horas. La evaluacion de elementos de estabilidad compatible incluye el color, la transparencia, el pH y el contenido de YC-6. Los resultados se muestran en las tablas que siguen.Two injection ampoules of YC-6 (5 ml X 2) of Example 1 are added to conventional infusions to evaluate the compatible stability of YC-6 in 8 hours. The evaluation of compatible stability elements includes color, transparency, pH and YC-6 content. The results are shown in the following tables.
Tabla 1. Pruebas de compatibilidad de la inyeccion de YC-6 e infusiones convencionales.Table 1. Compatibility tests of YC-6 injection and conventional infusions.
- ID ID
- Pruebas de compatibilidad (25 - 30 °C) Compatibility tests (25 - 30 ° C)
- A TO
- 5 ml de inyeccion de YC-6 X 2 + 250 ml de inyeccion de glucosa al 5% 5 ml of YC-6 X 2 injection + 250 ml of 5% glucose injection
- B B
- 5 ml de inyeccion de YC-6 X 2 + 250 ml de inyeccion de cloruro sodico al 0,9 % 5 ml of YC-6 X 2 injection + 250 ml of 0.9% sodium chloride injection
- C C
- 5 ml de inyeccion de YC-6 X 2 + 250 ml de inyeccion de glucosa y NaCl 5 ml of YC-6 X 2 injection + 250 ml of glucose and NaCl injection
- D D
- 5 ml de inyeccion de YC-6 X 2 + 500 ml de inyeccion de NaCl compuesto 5 ml of YC-6 X 2 injection + 500 ml of compound NaCl injection
- E AND
- 5 ml de inyeccion de YC-6 X 2 + 250 ml de inyeccion de bicarbonato sodico al 5 % 5 ml of YC-6 X 2 injection + 250 ml of 5% sodium bicarbonate injection
Tabla 2. Cambios de color y transparencia de infusiones convencionales.Table 2. Color changes and transparency of conventional infusions.
- ID ID
- Antes de la adicion Despues de la adicion (h) Before the addition After the addition (h)
- 0 2 4 8 0 2 4 8
- A TO
- Incolora, Incolora, Incolora, Incolora, Incolora, Colorless, Colorless, Colorless, Colorless, Colorless,
- transparente transparente transparente transparente transparente transparent transparent transparent transparent transparent
- B B
- Incolora, Incolora, Incolora, Incolora, Incolora, Colorless, Colorless, Colorless, Colorless, Colorless,
- transparente transparente transparente transparente transparente transparent transparent transparent transparent transparent
- C C
- Incolora, Incolora, Incolora, Incolora, Incolora, Colorless, Colorless, Colorless, Colorless, Colorless,
- transparente transparente transparente transparente transparente transparent transparent transparent transparent transparent
- D D
- Incolora, Incolora, Incolora, Incolora, Incolora, Colorless, Colorless, Colorless, Colorless, Colorless,
- transparente transparente transparente transparente transparente transparent transparent transparent transparent transparent
- E AND
- Incolora, Incolora, Incolora, Incolora, Incolora, Colorless, Colorless, Colorless, Colorless, Colorless,
- transparente transparente transparente transparente transparente transparent transparent transparent transparent transparent
Tabla 3. Cambios de pH de infusiones convencionales.Table 3. pH changes of conventional infusions.
- ID ID
- Antes de la adicion Despues de la adicion (h) Before the addition After the addition (h)
- 0 0
- 2 4 8 2 4 8
- A TO
- 4,05 4,06 4,05 4,02 4,08 4.05 4.06 4.05 4.02 4.08
- B B
- 5,60 5,62 5,58 5,46 5,58 5.60 5.62 5.58 5.46 5.58
- C C
- 4,02 4,04 4,03 4,00 4,04 4.02 4.04 4.03 4.00 4.04
- D D
- 5,64 5,62 5,60 5,59 5,59 5.64 5.62 5.60 5.59 5.59
- E AND
- 7,99 7,94 7,90 8,04 8,00 7.99 7.94 7.90 8.04 8.00
5 Tabla 4. Cambios de la concentracion de YC-6 en infusiones convencionales.5 Table 4. Changes in YC-6 concentration in conventional infusions.
- ID ID
- 0 h 2 h 8 h 24 h 0 h 2 h 8 h 24 h
- A TO
- 375,4 364,7 367,7 363,4 375.4 364.7 367.7 363.4
- B B
- 379,2 373,5 380,4 386,1 379.2 373.5 380.4 386.1
- C C
- 385,6 387,6 383,4 384,5 385.6 387.6 383.4 384.5
- D D
- 382,0 383,7 387,2 380,8 382.0 383.7 387.2 380.8
- E AND
- 386,7 375,1 381,3 376,5 386.7 375.1 381.3 376.5
Ejemplo 7. Evaluacion preliminar acerca de la seguridad de YC-6.Example 7. Preliminary assessment about the safety of YC-6.
Se enjaulan por peso ratones Kunming y se dividen en 5 grupos al azar. Cada grupo tiene 10 ratones, con la mitad machos y la otra mitad hembras. La inyeccion de YC-6 preparada en el Ejemplo 3 (20 mg/ml) es administrada i. v. a 10 traves de la vena de la cola en diferentes dosis. Todos los ratones se sacrifican despues de una semana de observacion. La reaccion toxica y el numero de muertes de los animales se registran todos los dfas. Se calcula la LD50 y una confianza del 95%. La LD50 de YC-6 es mas de 400 ± 121 mg/kg.Kunming mice are caged by weight and divided into 5 random groups. Each group has 10 mice, with half males and half females. The YC-6 injection prepared in Example 3 (20 mg / ml) is administered i. v. 10 through the tail vein in different doses. All mice are sacrificed after one week of observation. The toxic reaction and the number of animal deaths are recorded every day. The LD50 and 95% confidence are calculated. The LD50 of YC-6 is more than 400 ± 121 mg / kg.
Las celulas sangumeas se preparan de acuerdo con metodos convencionales con sangre fresca obtenida de conejos de Nueva Zelanda. Las celulas sangumeas se diluyen con solucion salina a una suspension al 2%. La inyeccion de 15 YC-6 preparada en el Ejemplo 1 se anade despues a la suspension al 2% y se incuba a 37 °C durante 3 horas. La tasa de hemolisis se determina usando un metodo colorimetrico. La tasa de hemolisis de la inyeccion de YC-6 es inferior al 1%.Blood cells are prepared according to conventional methods with fresh blood obtained from New Zealand rabbits. The blood cells are diluted with saline solution to a 2% suspension. The YC-6 injection prepared in Example 1 is then added to the 2% suspension and incubated at 37 ° C for 3 hours. The hemolysis rate is determined using a colorimetric method. The hemolysis rate of the YC-6 injection is less than 1%.
Los cobayos albinos son sometidos a la prueba anafilactica de acuerdo con los procedimientos convencionales. No se observa reaccion anafilactica despues de la administracion intravenosa de la inyeccion de YC-6 preparada en el Ejemplo 1.Albino guinea pigs are subjected to anaphylactic testing according to conventional procedures. No anaphylactic reaction is observed after intravenous administration of the YC-6 injection prepared in Example 1.
Se usan conejos de Nueva Zelanda para llevar a cabo una prueba de estimulacion vascular de la administracion 5 intravenosa de la inyeccion de YC-6 preparada en el Ejemplo 1. Los resultados muestran que los cambios tisulares de la vena del borde de la oreja son similares entre el grupo de tratamiento y el grupo de control. Cada conejo tiene una pared vascular integral de la vena del borde de la oreja y la estructura venosa normal. No se observa ningun cambio patologico, como el dano de las celulas endoteliales o el edema tisular circundante.New Zealand rabbits are used to perform a vascular stimulation test of intravenous administration of YC-6 injection prepared in Example 1. The results show that the tissue changes of the ear edge vein are similar. between the treatment group and the control group. Each rabbit has an integral vascular wall of the vein of the edge of the ear and the normal venous structure. No pathological change is observed, such as damage to endothelial cells or surrounding tissue edema.
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| CN101884638B (en) * | 2010-07-09 | 2011-11-09 | 中山大学 | Application of 5alpha-androstane-3beta,5,6beta-triol in preparing neuro-protective medicaments |
| CN103626818B (en) * | 2012-03-08 | 2016-03-30 | 广州市赛普特医药科技有限公司 | Androstane-3 β, 5 α, crystal-form compound of 6 beta-triols and preparation method thereof |
| CN103330946B (en) * | 2013-05-29 | 2015-03-25 | 广州市赛普特医药科技有限公司 | 5 alpha- androstane-3 beta, 5,6 beta-triol injection and preparation method thereof |
| CN104288110B (en) * | 2013-06-26 | 2017-05-10 | 广州市赛普特医药科技股份有限公司 | 5alpha-androstane-3beta,5,6beta-triol injection and preparing method thereof |
| US20160260519A1 (en) * | 2013-09-26 | 2016-09-08 | Polyone Corporation | Sustainable poly(vinyl halide) mixtures for thin-film applications |
| CN109985047B (en) * | 2017-12-29 | 2021-07-27 | 广州市赛普特医药科技股份有限公司 | Application of 5α-androsta-3β,5,6β-triol in the preparation of medicine for hemorrhagic stroke |
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| US2191576A (en) * | 1936-11-21 | 1940-02-27 | Soc Of Chemical Ind | 3,5,6-trihydroxy androstane and pregnane compounds |
| IE62095B1 (en) * | 1988-03-29 | 1994-12-14 | Univ Florida | Pharmaceutical formulations for parenteral use |
| FR2668945B1 (en) * | 1990-11-12 | 1993-02-19 | Theramex | NEW PROCESS FOR THE CRYSTALLIZATION OF ORGANIC SUBSTANCES AND THE COMPOUNDS THUS OBTAINED. |
| US5563131A (en) * | 1994-08-04 | 1996-10-08 | Pherin Corporation | Pregnane steroids as neurochemical initiators of change in human hypothalamic function and related pharmaceutical compositions and methods |
| CA2237023C (en) * | 1995-11-13 | 2008-02-19 | Supergen, Inc. | Improved formulation for administration of steroid compounds |
| US5824668A (en) * | 1996-11-07 | 1998-10-20 | Supergen, Inc. | Formulation for administration of steroid compounds |
| US20030060425A1 (en) * | 1998-11-24 | 2003-03-27 | Ahlem Clarence N. | Immune modulation method using steroid compounds |
| CN1232539C (en) * | 2002-05-10 | 2005-12-21 | 刘云清 | Match of organic medicine and beta-cyclodextrin derivative and its preparing process |
| WO2004070048A1 (en) * | 2003-02-07 | 2004-08-19 | Pharmacia & Upjohn Company Llc | A microbial process to prepare 5-androsten-3beta, 7alpha, 15alpha-triol-17-one and related analogues |
| CN1706501A (en) | 2005-05-27 | 2005-12-14 | 沈阳药科大学 | Preparation method of lipophilic drug cyclodextrin inclusion compound |
| CN101884638B (en) * | 2010-07-09 | 2011-11-09 | 中山大学 | Application of 5alpha-androstane-3beta,5,6beta-triol in preparing neuro-protective medicaments |
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